Method for producing 2-benzylaniline

ABSTRACT

2 -benzylaniline can be manufactured in one-pot reaction at a substantially reduced cost by allowing 2-amino-5-halogenobenzophenone to react under a reductive condition.

FIELD OF THE INVENTION

The present invention relates to a new method of manufacturing2-benzylaniline which is an important intermediate for pharmaceuticals.

BACKGROUND OF THE INVENTION

2-benzylaniline is an important compound as an intermediate material forpharmaceuticals. One of the known methods of manufacturing this compoundis to reduce 2-aminobenzophenone with metallic sodium or hydrazine (J.Chem. Soc., 292, 1948; Chem. Ber., 96, 765, 1963). However, the starting2-aminobenzophenone used therefor is difficult to obtain, and further,the cost of 2-aminobenzophenone is relatively high. Therefore, there hasbeen a demand to develop a less expensive manufacturing method forindustrial use.

Another method is known which applies Friedel-Crafts reaction-to2-aminobenzylchloride hydrochloride and benzene by using aluminumchloride (Chem. Ber., 61, 2276, 1928). Another known method is to reduceo-nitrodiphenyl methane obtained by Friedel-Crafts reaction using2-nitrobenzylchloride and benzene with aluminum chloride (J. Am. Chem.Soc., 53, 1428, 1931). However, benzene is a carcinogenic material andits safety problem remains unsolved in industrial production.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a new and industriallyadvantageous method of manufacturing 2-benzylaniline.

To solve the aforementioned problems, the present inventors have made astrenuous effort and have found out a method of simultaneouslyperforming dehalogenation and hydrogenation of a carbonyl group under areductive condition. The method uses 2-amino-5-halogenobenzophenone as astarting material which is less expensive and easily obtainable.

Generally, in the dehalogenation reaction by catalytic reduction, basicconditions are used to promote the reaction. In hydrogenation of acarbon-oxygen bond, for example, in the case of benzophenone, thereaction is inhibited at the phase of benzhydrol under basic conditions.Acidic conditions must be used in order to promote the reaction and toreduce benzhydrol to methylene. As a result, normally, dehalogenationand hydrogenation of a carbon-oxygen bond must be carried out in twostages: under basic conditions and under acidic conditions.

The present inventors have found out that catalytic reduction tomethylene by hydrogenation of a carbon-oxygen bond and dehalogenationproceed at one time, starting from 2-amino-5-halogenobenzophenone underbasic conditions where catalytic reduction (hydrogenation) to methylenecannot normally be expected, or under neutral conditions (which indicatethe conditions without intentionally adding an acid for hydrogenation ofa carbon-oxygen bond). It is surprising that these two differentreactions occur simultaneously under a reductive condition from2-amino-5-halogenobenzophenone using a palladium or a palladium/carboncatalyst with hydrogen, and 2-benzylaniline is obtained in high yield inone-pot reaction.

In the manufacturing method of the present invention, although therecoexist 2-aminobenzophenone as a dehalogenated product,2-amino-5-halogenobenzhydrol obtained by reduction of a carbonyl group,2-aminobenzhydrol obtained in further advanced stage of reduction and2-amino-5-halogenobenzophenone as a reaction intermediate, they arefully reduced to 2-benzylaniline and 2-benzylaniline is obtained in highyield.

To be more specific, the method according to the present inventionprovides:

-   -   (1) A method of manufacturing 2-benzylaniline, wherein        2-amino-5-halogenobenzophenone is reacted under a reductive        condition.    -   (2) The method of manufacturing 2-benzylaniline described in the        aforementioned method (1), wherein an organic solvent or a        water-containing organic solvent is used as a solvent for the        reaction.    -   (3) The method of manufacturing 2-benzylaniline described in the        aforementioned method (1) or (2), wherein the reaction is        carried out under a reductive condition using a palladium        catalyst.    -   (4) The method of manufacturing 2-benzylaniline described in the        aforementioned method (3), wherein a base is added.    -   (5) The method of manufacturing 2-benzylaniline described in the        aforementioned method (3), wherein an amphoteric compound is        further added.    -   (6) The method of manufacturing 2-benzylaniline described in the        aforementioned method (1), wherein a palladium-carbon catalyst        in dimethylformamide is used in the reaction.    -   (7) The method of manufacturing 2-benzylaniline described in the        aforementioned method (6), wherein a base is added.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows 2-amino-5-halogenobenzophenone (where X denotes a halogenatom); and

FIG. 2 shows 2-benzylaniline.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The reaction of the present invention is carried out by adding areducing agent after mixing a starting material and a solvent, and ifrequired, additionally mixing a base or an amphoteric compound. Anorganic solvent is used for extraction, then the extract is washed withwater and concentrated, whereby crude 2-benzylaniline is obtained. It ispurified, if required, by distillation under a reduced pressure (orpurified by recrystallization or by other appropriate methods), wherebypure 2-benzylaniline can be produced.

When an organic solvent is used, an aprotic solvent such asdimethylformamide and N-methylpyrrolidone, an ether type solvent such astetrahydrofuran and diglyme, an alcohol type solvent such as ethanol and2-propanol, and a hydrocarbon solvent such toluene and xylene areutilized. A solution consisting the mixture thereof can also be used.Preferably used are, dimethylformamide, N-rmethylpyrrolidone andtetrahydrofuran because of their excellent solubility for2-amino-5-halogenobenzophenone. Among them, dimethylformamide is morepreferably used. The amount of a solvent to be used is 1 through 50-foldvolume, preferably 2 through 10-fold volume, more preferably 5-foldvolume with respect to the weight of 2-amino-5-halogenobenzophenone.Water may be added to improve the solubility of a salt withhydrochloride generated by the reaction. Its amount of use is 0.1through 20-fold volume, preferably 0.5 through 5-fold volume, and morepreferably 2-fold volume.

From the viewpoint of industrial production, a hydrogenation reaction ispreferably used as a reductive condition because it does not produce awaste product. The catalyst used for the hydrogenation reaction ispreferably a palladium catalyst, more preferably a palladium/carboncatalyst. The amount of catalyst to be used is 0.1 through 50 percent byweight, preferably 0.5 through 10 percent by weight, and more preferably1 through 7.5 percent by weight, with respect to the weight of2-amino-5-halogenobenzophenone. If it is less than 0.1 percent, thereaction will be too slow. If it is over 50 percent, the cost will betoo high.

When a catalyst is used for hydrogenation, pressurized hydrogenconditions are preferred in order to reduce reaction time, althoughreaction will take place under an atmospheric pressure. The hydrogenpressure is 0.1 through 15 MPa, preferably 0.5 through 10 MPa and morepreferably 1 through 5 MPa.

When hydrogenation reaction is performed, 2-benzylaniline acts as aneutralizing agent of hydrochloric acid generated during the reaction,therefore dehalogenation reaction will take place without adding a base.Since 2-amino-5-halogenobenzylaniline tends to remain at the end of thereaction, a base may be added. The preferred base includes an inorganicbase such as alkaline metallic hydroxide and alkaline metalliccarbonate, and an organic base such as alkaline metallic acetate,triethylamine, N-methyl morpholine and pyridine. More preferred baseincludes potassium carbonate and triethylamine. The amount of the baseto be used is 0.1 through 1.0 mole equivalent with respect to2-amino-5-halogenobenzophenone, preferably 0.3 through 0.9, and morepreferably 0.6 through 0.8.

When more than 1.0 mole equivalent is used, the basicity of the reactionsolution will be increased and the dehalogenation reaction will takeplace faster, however, the remaining amount of 2-aminobenzhydrol will beincreased. When 2-amino-5-halogenobenzhydrol and2-amino-5-halogenobenzylaniline as intermediates are required toeliminate completely, 1.0 mole equivalent or more of base is used. Aftermaking sure that there is almost no absorption of hydrogen, an acidcomponent such as an acetic acid is added so that the reaction solutionwill be acidic, and hydrogenation is continued. Instead of base, anamphoteric compound may be used. Use of amino acid andalkylaminosulfonic acid is preferred. More preferred are alanine andtaurine. The amount of the amphoteric compound to be used should be 1.0through 10.0 mole equivalent with respect to2-amino-5-halogenobenzophenone, and preferably 1.0 through 3.0 moleequvalent.

In the case of hydrogenation reaction, the reaction temperature is 0through 100° C., preferably 10 through 90° C. and more preferably 20through 60° C. The reaction time varies according to the amount of thesolvent, catalyst and basic substance, hydrogen pressure andtemperature. Normally, reaction time is 1 through 30 hours andgenerally, 3 through 6 hours. Further, in addition to the aforementioned2-amino-5-halogenobenzylaniline, 2-amino-5-halogenobenzhydrol and2-aminobenzhydrol as reaction intermediates tend to remain in thehydrogenation reaction under basic conditions. Accordingly, if anexcessive hydrogenation reaction is carried out until they arecompletely reduced, aromatic nucleus will be hydrogenated, resulting indecrease of yield. Thus, the reaction is preferably terminated so thatthe remaining amount of the aforementioned2-amino-5-halogenobenzylaniline, 2-amino-5-halogenobenzhydrol or2-aminobenzhydrol will be about 0.1 through 1.5%.

The progress of reaction can be measured by chromatography with highefficiency. The liquid chromatography measuring conditions are as givenbelow:

Column: Symmetry C18, 4.6×150 mm

Eluant: Acetonitrile/0.3% phosphate aqueous solution: 6/4

Flow rate: 1.0 ml/min.

Detector: UV 254 nm

Thermostatic bath temperature: 40° C.

EXAMPLES

The present invention will be described with reference to examples,however, the present invention is not restricted thereto.

Example 1

37.5 g of 2-amino-5-chlorobenzophenone and 188 ml of dimethylformamidewere added into a 500 ml autoclave (by Hastelloy Inc.) equipped with anagitator and a thermometer, and 5.63 g of 10% palladium carbon (M type)(wet type, water: 55±5 wt %) by Kawaken Fine Chemical Inc. was thenadded. Air in the autoclave was replaced by nitrogen and then byhydrogen. After that, the reaction was performed at a hydrogen pressureof 3.0 MPa, a reaction temperature of 30 through 35° C. and an agitationspeed of 1000 through 1100 rpm. About one hour later, the hydrogenabsorption speed was reduced, and heating was applied until about 60° C.was reached. Further about one hour later, when there was almost nohydrogen absorption, cooling was carried out to reduce the temperatureto the room temperature. The contents were then transferred into a 500ml flask. The catalyst was removed by filtering with a pressure filter,and the catalyst was washed with 19 ml of dimethylformamide. Then, 200ml of toluene, 38.8 g of 25% sodium hydroxide aqueous solution and 50 mlof water were added to the filtrate and were agitated. After that, itwas transferred into a separate solution funnel, and the water layer wasremoved. The organic layer was washed three times with 50 ml of water.The extracted solution was concentrated under a reduced pressure and30.1 gram of brown oil was obtained. The brown oil was subjected todistillation under a reduced pressure (0.6 KPa and 170° C.) to get 26.7g of 2-benzylaniline.

Yield rate: 90.1%

HPLC purity: 98.7%

MS m/z=183 (molecule ion peak)

1H-NMR (CDCl3) σ3.4-3.6 (broad, 2H, —NH2), 3.9 (s, 2H, —CH2-), 6.7-7.3(m, 9H, aromatics)

Example 2

37.5 g of 2-amino-5-chlorobenzophenone, 20.3 g of taurine and 188 ml ofdimethylformamide were added into a 500 ml autoclave (by Hastelloy Inc.)equipped with an agitator and a thermometer, and 5.63 g of 10% palladiumcarbon (M type) (wet type, water: 55±5 wt %) by Kawaken Fine ChemicalInc. was then added. Air in the autoclave was replaced by nitrogen andthen by hydrogen. After that, the reaction was performed at a hydrogenpressure of 3.0 MPa, a reaction temperature of 30 through 35° C. and anagitation speed of 1000 through 1100 rpm. About two hours later, thehydrogen absorption speed was reduced, and heating was applied untilabout 50° C. was reached. About another hour later, when there wasalmost no hydrogen absorption, cooling was carried out to reduce thetemperature to the room temperature. The contents were then transferredinto a 500 ml flask. The catalyst was removed by filtering with apressure filter, and the catalyst was washed with 19 ml ofdimethylformamide. Then, 200 ml of toluene, 38.8 g of 25% sodiumhydroxide aqueous solution and 75 ml of water were added to the filtrateand were agitated. After that, it was transferred into a separatesolution funnel, and the water layer was removed. The organic layer waswashed three times with 50 ml of water. The extracted solution wasconcentrated under a reduced pressure and 30.7 g of brown oil wasobtained. The brown oil was subjected to distillation under a reducedpressure (0.6 KPa and 170° C.) to get 27.1 g of 2-benzylaniline.

Yield rate: 91.2%

HPLC purity: 98.7%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 3

37.5 g of 2-amino-5-chlorobenzophenone, 15.8 ml of triethylamine and 188ml of dimethylformamide were added into a 500 ml autoclave (by HastelloyInc.) equipped with an agitator and a thermometer, and 1.88 g of 10%palladium carbon (M type) (wet type, water: 55±5 wt %) by Kawaken FineChemical Inc. was then added. Air in the autoclave was replaced bynitrogen and then by hydrogen. After that, the reaction was performed ata hydrogen pressure of 3.0 MPa, a reaction temperature of 30 through 35°C. and an agitation speed of 1000 through 1100 rpm. About three hourslater, the hydrogen absorption speed was reduced, and heating wasapplied until about 45° C. was reached. About five hours later, whenthere was almost no hydrogen absorption, cooling was carried out toreduce the temperature to the room temperature. The contents were thentransferred into a 500 ml flask. The catalyst was removed by filteringwith a pressure filter, and the catalyst was washed with 19 ml ofdimethylformamide. Then, 200 ml of toluene, 19.4 g of 25% sodiumhydroxide aqueous solution and 50 ml of water were added to the filtrateand were agitated. After that, it was transferred into a separatesolution funnel, and the water layer was removed. The organic layer waswashed three times with 50 ml of water. The extracted solution wasconcentrated under a reduced pressure and 29.7 g of brown oil wasobtained. The brown oil was subjected to distillation under a reducedpressure (0.6 KPa and 170° C.) to get 28.0 g of 2-benzylaniline.

Yield rate: 94.6%

HPLC purity: 98.8%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 4

25.0 g of 2-amino-5-chlorobenzophenone, 8.2 g of potassium carbonate,150 ml of dimethylformamide and 50 ml of water were added into a 500 mlautoclave (by Hastelloy Inc.) equipped with an agitator and athermometer, and 3.75 g of 10% palladium carbon (M type) (wet type,water: 55±5 wt %) by Kawaken Fine Chemical Inc. was then added. Air inthe autoclave was replaced by nitrogen and then by hydrogen. After that,the reaction was performed at a hydrogen pressure of 3.0 MPa, a reactiontemperature of 30 through 35° C. and an agitation speed of 1000 through1100 rpm. About twelve hours later, when there was almost no hydrogenabsorption, cooling was carried out to reduce the temperature to theroom temperature. The contents were then transferred into a 500 mlflask. The catalyst was removed by filtering with a pressure filter, andthe catalyst was washed with 12 ml of dimethylformamide. Then, 130 ml oftoluene, was added to the filtrate and was agitated. After that, it wastransferred into a separate solution funnel, and the water layer wasremoved. The organic layer was washed three times with 30 ml of water.The extracted solution-was concentrated under a reduced pressure and21.0 g of brown oil was obtained. The brown oil was subjected todistillation under a reduced pressure (0.6 KPa and 170° C.) to get 16.8g of 2-benzylaniline.

Yield rate: 85.1%

HPLC purity: 98.4%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 5

37.5 g of 2-amino-5-chlorobenzophenone, 12.3 g of potassium carbonate,113 ml of dimethylformamide and 75 ml of water were added into a 500 mlautoclave (by Hastelloy Inc.) equipped with an agitator and athermometer, and 5.63 g of 10% palladium carbon (M type) (wet type,water: 55±5 wt %) by Kawaken Fine Chemical Inc. was then added. Air inthe autoclave was replaced by nitrogen and then by hydrogen. After that,the reaction was performed at a hydrogen pressure of 3.0 MPa, a reactiontemperature of 30 through 35° C. and an agitation speed of 1000 through1100 rpm. About seven hours later, it was confirmed that the hydrogenabsorption speed was reduced, and 14 ml of acetic acid was added tocontinue reaction for five hours. Since there was almost no hydrogenabsorption, cooling was carried out to reduce the temperature to theroom temperature. The contents were then transferred into a 500 mlflask. The catalyst was removed by filtering with a pressure filter, andthe catalyst was washed with 19 ml of dimethylformamide. Then, 200 ml oftoluene, 38.8 g of 25% sodium hydroxide aqueous solution and 50 ml ofwater were added to the filtrate and were agitated. After that, it wastransferred into a separate solution funnel, and the water layer wasremoved. The organic layer was washed three times with 50 ml of water.The extracted solution was concentrated under a reduced pressure and28.7 g of brown oil was obtained. The brown oil was subjected todistillation under a reduced pressure (0.6 KPa and 170° C.) to get 24.1g of 2-benzylaniline.

Yield rate: 81.4%

HPLC purity: 98.5%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 6

37.5 g of 2-amino-5-chlorobenzophenone, 15.8 ml of triethylamine and 188ml of N-methylpyrrolidone were added into a 500 ml autoclave (byHastelloy Inc.) equipped with an agitator and a thermometer, and 1.88 gof 10% palladium carbon (M type) (wet type, water: 55±5 wt %) by KawakenFine Chemical Inc. was then added. Air in the autoclave was replaced bynitrogen and then by hydrogen. After that, the reaction was performed ata hydrogen pressure of 3.0 MPa, a reaction temperature of 30 through 35°C. and an agitation speed of 1000 through 1100 rpm. About three hourslater, the hydrogen absorption speed was reduced, and heating wasapplied until about 45° C. was reached. About two hours later, whenthere was almost no hydrogen absorption, cooling was carried out toreduce the temperature to the room temperature. The contents were thentransferred into a 500 ml flask. The catalyst was removed by filteringwith a pressure filter, and the catalyst was washed with 19 ml ofN-methylpyrrolidone. Then, 200 ml of toluene, 19.4 g of 25% sodiumhydroxide aqueous solution and 50 ml of water were added to the filtrateand were agitated. After that, it was transferred into a separatesolution funnel, and the water layer was removed. The organic layer waswashed three times with 50 ml of water. The extracted solution wasconcentrated under a reduced pressure and 32.1 g of brown oil wasobtained. The brown oil was subjected to distillation under a reducedpressure (0.6 KPa and 170° C.) to get 27.5 g of 2-benzylaniline.

Yield rate: 92.9%

HPLC purity: 98.5%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 7

37.5 g of 2-amino-5-chlorobenzophenone, 15.8 ml of triethylamine and 188ml of tetrahydrofuran were added-into a 500 ml autoclave (by HastelloyInc.) equipped with an agitator and a thermometer, and 1.88 g of 10%palladium carbon (M type) (wet type, water: 55±5 wt %) by Kawaken FineChemical Inc. was then added. Air in the autoclave was replaced bynitrogen and then by hydrogen. After that, the reaction was performed ata hydrogen pressure of 3.0 MPa, a reaction temperature of 30 through 35°C. and an agitation speed of 1000 through 1100 rpm. About two hourslater, the hydrogen absorption speed was reduced, and heating wasaaplied until about 45° C. was reached. About one hour later, when therewas almost no hydrogen absorption, cooling was carried out to reduce thetemperature to the room temperature. The contents were then transferredinto a 500 ml flask. The catalyst was removed by filtering with apressure filter, and the catalyst was washed with 19 ml oftetrahydrofuran. Then, 200 ml of toluene, 19.4 g of 25% sodium hydroxideaqueous solution and 50 ml of water were added to the filtrate and wereagitated. After that, it was transferred into a separate solutionfunnel, and the water layer was removed. The organic layer was washedthree times with 50 ml of water. The extracted solution was concentratedunder a reduced pressure and 29.5 g of brown oil was obtained. The brownoil was subjected to distillation under a reduced pressure (0.6 KPa and170° C.) to get 27.8 g of 2-benzylaniline.

Yield rate: 93.9%

HPLC purity: 98.8%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

Example 8

37.5 g of 2-amino-5-chlorobenzophenone, 15.8 ml of triethylamine and 188ml of dimethylformamide were added into a 500 ml autoclave (by HastelloyInc.) equipped with an agitator and a thermometer, and 0.38 g ofpalladium black by Kawaken Fine Chemical Inc. was then added. Air in theautoclave was replaced by nitrogen and then by hydrogen. After that, thereaction was performed at a hydrogen pressure of 3.0 MPa, a reactiontemperature of 30 through 35° C. and an agitation speed of 1000 through1100 rpm. Since there was almost no hydrogen absorption about threehours later, cooling was carried out to reduce the temperature to theroom temperature. The contents were then transferred into a 500 mlflask. The catalyst was removed by filtering with a pressure filter, andthe catalyst was washed with 19 ml of dimethylformamide. Then, 200 ml oftoluene, 19.4 g of 25% sodium hydroxide aqueous solution and 50 ml ofwater were added to the filtrate and were agitated. After that, it wastransferred into a separate solution funnel, and the water layer wasremoved. The organic layer was washed three times with 50 ml of water.The extracted solution was concentrated under a reduced pressure and30.3 g of brown oil was obtained. The brown oil was subjected todistillation under a reduced pressure (0.6 KPa and 170° C.) to get 27.0g of 2-benzylaniline.

Yield rate: 91.2%

HPLC purity: 98.9%

The spectra according to the mass spectrometry and nuclear magneticresonance spectroscopy were the same as that of the 2-benzylanilineobtained in EXAMPLE 1.

In the Examples 1 through 8, the amount of2-amino-5-halogenobenzylaniline, 2-amino-5-halogenobenzhydrol and2-aminobenzhydrol in the reaction solution at the end of reaction wasdetermined under the aforementioned chromatographic conditions. They areall within the range of 0.2 through 1.0%.

POSSIBILITY OF INDUSTRIAL APPLICATION

The manufacturing method of the present invention allows 2-benzylanilineto be manufactured in one-pot reaction without using hazardoussubstrates and without isolating the reaction intermediates, achievingin substantial reduction of the manufacturing cost.

1. A method of manufacturing 2-benzylaniline, comprising the step of:allowing 2-amino-5-halogenobenzophenone to react under a reductivecondition.
 2. The method of manufacturing 2-benzylaniline of claim 1,wherein an organic solvent or a water-containing organic solvent isfurther used as a solvent for the reaction.
 3. The method ofmanufacturing 2-benzylaniline of claim 1, wherein the reaction iscarried out under the reductive condition using a palladium catalyst. 4.The method of manufacturing 2-benzylaniline of claim 3, wherein a baseis further added.
 5. The method of manufacturing 2-benzylaniline ofclaim 3, wherein an amphoteric compound is further added.
 6. The methodof manufacturing 2-benzylaniline of claim 1, wherein a palladium-carboncatalyst in dimethylformamide is used in the reaction.
 7. The method ofmanufacturing 2-benzylaniline of claim 6, wherein a base is furtheradded.
 8. The method of manufacturing 2-benzylaniline of claim 2,wherein the reaction is carried out under the reductive condition usinga palladium catalyst.
 9. The method of manufacturing 2-benzylaniline ofclaim 8, wherein a base is further added.
 10. The method ofmanufacturing 2-benzylaniline of claim 8, wherein an amphoteric compoundis further added.